Pharmacotherapy for Substance Use Disorders

Vanessa de la Cruz, MDChief of PsychiatryMental Health and Substance Abuse ServicesSanta Cruz County Health Services Agency1400 Emeline AvenueSanta Cruz, CA 95060delacrv@health.co.santa-cruz.ca.us(831)454-4885

What is addiction?

Addiction can be defined as compulsive drug use despite negative consequences

What is addiction?

Physiologic dependence and withdrawal avoidance do not explain addiction

Neurobiology of addiction attempts to explain the mechanisms by which drug seeking behaviors are consolidated into compulsive use:-long persistence of relapse risk-drug-associated cues control behavior

Although addictive drugs are pharmacologically diverse… Stimulants (act as a serotonin-

norepinephrine-dopamine reuptake inhibitors) Cocaine, amphetamines, MDMA

Opioids (agonist action) Heroin, morphine, oxycodone, fentanyl

GABAergic agonists/modulators Alcohol, benzodiazepines, barbiturates

Cannabis (binds cannabinoid receptors)

…they all lead to a common pathway All addictive drugs pharmacologically

release dopamine in the nucleus accumbens

The dopamine system

The Dopamine Reward PathwayHow Dopamine leads to behavior change Dopamine required for natural stimuli

(food, opportunity for mating, etc) to be rewarding and drive behavior

Natural rewards and addictive drugs both cause dopmine release in the Nucleus Acumbens

Addictive drugs mimic effects of natural rewards and thus shape behavior

The Dopamine Reward PathwayHow Dopamine leads to behavior change Survival demands that organisms find

and obtain needed resources (food, shelter) and opportunity for mating despite risks -survival relevant goals

These goals have natural “rewards” (eating, safety, sex)

Behaviors with rewarding goals persist to a conclusion and increase over time as they are positively reinforcing

The Dopamine Reward PathwayHow Dopamine leads to behavior change Internal states (hunger) increase

value of goal-related cues and increase pleasure of consumption

likelihood that complex behavioral sequence (hunting) will be brought to successful conclusion

The Dopamine Reward PathwayHow Dopamine leads to behavior change Behavioral sequences involved in

obtaining reward (steps required to hunt) become overlearned/automatized

Automatized behavioral repertoires can be activated by cues predictive of reward

Prediction Error Hypothesis

Exposure to an unexpected reward causes transient firing of dopamine neurons which signals brain to learn a cue.

Once cue is learned, burst of firing occurs at cue, not at reward.

If the reward does not arrive, dopamine firing will decrease below baseline levels serves as an error signal about reward predictions

If reward comes at unexpected time, dopamine firing will increase positive predictive error signal: “better than expected!”

Dopamine Gating Hypothesis• Because drugs cause dopamine release (due to

pharmacological actions), dopamine firing upon use does not decay over time brain repeatedly gets positive predictive error signal: “better than expected!”

• Drug cues become ubiquitous (drug cues difficult to extinguish)

• Cues that predict drug availability take on enormous incentive salience (consolidates drug seeking behavior)

• Drug cues will become powerfully overweighted compared to other choices (contributes to loss of control over drug use)

Cue Learning

Glutamate is another excitatory neurotransmitter involved in cue learning: Specific information about cues Evaluation of cue significance Learned motor responses

Enhances dopamine dependant learning

Source: Am J Psychiatry 2005;162:1414-1422

Clinical Implications Addictive behaviors are a important

and normal part of human behavior Addictive drugs pharmacologically

modify functioning of reward circuits to overvalue drug rewards and reduce the comparative value of other rewards

Intention to stop use is not enough to stably quit substance use.

4 FDA approved medications for Alcohol Dependence Naltrexone oral (Revia) Naltrexone injection (Vivetrol) Acamprosate (Camprel) Disulfiram (Antabuse)

Naltrexone (Revia)

opiate antagonist Prevents dopamine release normally

produced by alcohol consumption All other effects of alcohol still occur Reduces reward associated with

alcohol use, leading to extinction of alcohol seeking behaviors

Less binge drinking, craving is reduced

Naltrexone (Revia)

50-100 mg QD Side effects: nausea, vomiting,

headaches, dizziness, fatigue, insomnia, somnolence, anxiety

Caution/avoid: opioid agonists, acute hepatitis, liver failure

Naltrexone (Vivetrol)

Same profile as oral Risk of injection site reaction Caution/avoid if: thrombocytopenia,

coagulation disorder, inadequate muscle mass

380 mg IM q month

Acamprosate (Campral)

Pharmacologically “messy” Has effects on glutamatergic and

GABAergic systems Seems to reduce cravings via an

undetermined mechanism Works best in abstinent patients to

prevent relapse

Acamprosate (Campral)

Side effects: diarrhea (common), anxiety, weakness, insomnia, depression, suicidality

Requires kidney function monitoring if renal impairment or elderly

Caution/avoid if: renal impairment 666 mg TID

Disulfiram (Antabuse)

Aversive agent Inhibits enzyme that that breaks

down acetaldehyde (alcohol byproduct that causes flushing, nausea, and palpitations)

To avoid feeling sick, people will avoid drinking

Only works if you take it, works best if dosing can be observed

Disulfiram (Antabuse)

Must be abstinent for 24 hours to start 250 mg QD Side effects: hepatoxicity, perpheral

neuropathy, psychosis, delirium, disulfriam/alcohol reaction

Monitor liver function Caution/avoid: severe

liver/cardiac/respiratory disease, severe psychiatric disorder, metronidizole

Opiate Replacement Therapy Methadone Buprenorphine

All most effective when combined with counseling and monitored treatment

Methadone

Opioid substitution therapy Long acting synthetic mu opiod Slow onset Interacts with many medications Risk of prolonged QT interval Must be admitted to an opioid

treatment program

Methadone

Side effects: dizziness, sedation, nausea, vomiting, sweating, constipation, swelling, sexual dysfunction, respiratory depression, EKG changes

Get baseline EKG Caution/avoid: patient enrolled at

another OTP, liver failure, use of opioid antagonists, benzodiazepine use, cardiac arrythmias

Buprenorphine

Partial opioid agonist-less reinforcing than full agonist, milder effects-easier withdrawal-safety- overdose ceiling effect

High affinity to the opiate receptor Long duration of action Suboxone = buprenorphine coated

with nalaoxone (Narcan)

Buprenorphine

Side effects: dizziness, sedation, nausea, vomiting, sweating, constipation, liver disease, sexual dysfunction, respiratory depression, precipitated withdrawal

Hepatic metabolism- monitor LFT’s Caution/avoid: patient on full agonist

opiods, benzodiazepines, naltrexone, respiratory/liver/renal impairment

Store out of reach of children

Methadone vs. Buprenorphine-clinic only -office based

-requires daily visits-can see MD every 30 days

-high level monitoring -limited monitoring

-observed dosing -self dosing

-treats severe pain -treats for mild-mod pain

-many drug interactions -minimal drug interactions

-can be sedating -minimally sedating

-can be euphorigenic -minimally euphorigenic

-safety concerns -safety: ceiling effect

-blocks opiate use -blocks opiate use

Behavioral Treatments for Substance Use Disorders

Behavioral Treatments for Substance Use Disorders Motivational Interviewing

Focuses on exploring and resolving ambivalence and centers on motivational processes within individual that facilitate change

Supports change in a manner congruent with a persons own values and concerns

Behavioral Treatments for Substance Use Disorders Behavioral Couples Counseling

Focuses on reduced alcohol or drug use in patient and improving overall relationship satisfaction

Series of behavioral assignments to increase positive feelings, shared activities, constructive communication

May include sobriety contract: urine drug screens, session attendance, 12-step participation

Behavioral Treatments for Substance Use Disorders Community Reinforcement Approach

(CRA) Comprehensive cognitive behavioral

intervention that focuses on environmental contingencies that impact and influence behavior

Build motivation, initiate sobriety, analyze use pattern, increase positive reinforcement, learn new coping skills, occupational rehab, involve significant other

Behavioral Treatments for Substance Use Disorders Contingency Management

Non-monetary or monetary rewards made contingent on objective evidence

“pay people for clean urines”

Behavioral Treatments for Substance Use Disorders Twelve Step Facilitation

brief, structured, and manual-driven approach to facilitating early recovery from alcohol abuse, alcoholism, and other drug abuse and addiction problems

implemented over 12 to 15 sessions. based on the behavioral, spiritual, and cognitive principles

of 12-step fellowships such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA)

Source: VA/DoD Clinical Practice Guideline: Management of Substance Use Disorders

References/Resources/Recommended Reading

Addiction: A Disease of Learning and Memory. Am J Psychiatry 2005;162:1414-1422

Health Services for VA Patients with Substance Use Disorders: Comparison of Utilization in Fiscal Years 2011, 2010, and 2002 (draft)

Confrontation in Addiction Treatment, William R. Miller, PhD and William White, MA (http://www.cafety.org/miscellaneous/755-confrontation-in-addiction-treatment)

VA/DoD Clinical Practice Guideline: Management of Substance Use Disorders (www.healthquality.va.gov/sud/sud_full_601f.pdf)

National Survey on Drug Use and Health (NSDUH) https://nsduhweb.rti.org/

Substance Abuse & Mental Health Services Administration http://www.samhsa.gov/